5-carbocyclic-3-imidomethyloxazolidines and process



United States Patent This invention relates to5-carbocyclic-3-imidoalkyloxazolidines and a process for the manufacturethereof. More particularly, this invention relates to oxazolidines ofthe formula 0 I E --N wherein E represents either an aryl or cycloalkylradical; E" represents either hydrogen or a saturated mono,- valenthydrocarbon radical; T represents an alkylene radical; and Z representsan alkylene, alkenylene, or ortho-divalent monocarbocyclic radicalconsisting of 6 annular carbon atoms to which more than 3 and fewer than11 hydrogen atoms are attached.

Among the aryl radicals represented by E, especially phenyl and naphthylradicals optionally substituted by l or more halogens and/ or alkyl and/or alkoxy radicals are preferred. Illustrative of such radicals but notdelimiting are phenyl, halophenyl, (lower alkoxy)phenyl, and poly(loweralkoxy)phenyl radicals. Inasmuch as the radicals referred to areunexceptionably named in accordance with recommendations of theInternational Union of Pure and Applied Chemistry and Chemical Abstracts(cf. specifically section 75 of the Introduction, With Key andDiscussion of the Naming of Chemical Compounds for Indexing, ChemicalAbstracts, 39, 5867 if, with respect to compound radical names), thoseskilled 'in the art will readily recognize that halophenyl radicals areradicals of the formula halogen (lower alkoxy)phenyl radicals areradicals of the formula O-lower alkyl and poly(lower alkoxy)phenylradicals are radicals of the formula wherein n is a positive integeramounting to less than 9, typical of such groupings being methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentylisopentyl, neopentyl, hexyl, isohexyl, heptyl, and octyl radicals.

3,081,308 Patented Mar. 12, 1963 When E in the generic formula forcompounds of this invention represents a cycloalkyl radical,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptylradicals will be understood, the cyclohexyl grouping being preferred.

By saturated monovalent hydrocarbon radicals (cf.

definition of E above), is meant either an alkyl radical--desirably oflower orderor a cycloalkyl radical.

The alkylene radicals represented by T in the generic formula also aredesirably of lower order, for example, methylene, ethylene,trimethylene, propylene, tetrarnethylene, 2,2-dimethyl-1,3-propylene,and like bivalent saturated acyclic straightor branched-chain hydrocarbon groupings of empirical formula wherein n is a small positiveinteger.

The alkylene radicals represented by Z in the generic formula areoptimally lower alkylene radicals separating the groups attached theretoby either 2 or 3 carbon atoms, and thus giving rise to succinimides llower alkyl) 11 and glutarimides lower alkyl) 1:

n 2n-2 (n being a positive integer) are comprehended, especiallyvinylene radicals C H which give rise to unsubstituted maleimidesFinally, when Z represents an ortho-divalent monocarbocyclic radicalconsisting of 6 annular carbon atoms and more than 3 and fewer than 11hydrogen atoms attached thereto, the compounds comprising it arenecessarily cyclohexane-l,Z-dicarboximides,

and 2,6-cyclohexadiene-l,Z-dicarboximides or phthalimides Equivalent tothe foregoing compounds for the purposes of this invention are non-toxicacid addition salts thereof, which can be enformulated wherein E, E", T,and Z have the meanings previously assigned, and Q is one equivalent ofan anion, for example, chloride, bromide, iodide, nitrate, phosphate,sulfate, sulfamate, methyl sulfate, ethyl sulfate, benzenesulfonate,toluenesulfonate, acetate, lactate, succinate, malate, maleate,tartrate, citrate, gluconate, ascor-bate, benzoate, cinnamate, or thelikewhich in combination with the cationic portion of a salt aforesaid,is neither pharmacologically nor otherwise undesirable in pharmaceuticaldosage.

The compounds to which this invention relates are useful because oftheir valuable pharmacological properties. They are characterized byexceptionally potent anorectic, diuretic, and anti-inflammatoryactivities, the last-named activity being manifest by a substantialcapacity to inhibit the heat, swelling, redness, and granuloma-formationcharacteristic of the inflammatory response to tissue injury. Moreover,the compounds hereof are anti-biotic and anti-fungal agents effectiveagainst a variety of pathogenic microorganisms, among them being E.coli, B. subtilis, and T richophyton mentagrophytes.

Those skilled in the art will appreciate that the carbon atom inposition of the oxazolidine ring in the instant compounds is asymmetric;and, accordingly, the compounds exist in a minimum of 2 optically activeand 1 racemic forms. When the carbon in position 4 is substituted, anadditional 2 optically active and 1 racemic forms occur. The relativepharmacological potency of the various forms can and does varyappreciably. Thus, the oxazolidines of this invention derived fromdextronorephedrine-for example, the corresponding 4-methyl-5-phenyl-3-phthalimidomethyloxazolidine produce an unexpectedly superiorand selective anti-inflammatory effeet in the animal body.

Manufacture of the imidomethyl compounds hereinafter claimed proceeds byheating an appropriately-substituted oxazolidine of the formula whereinE and E" are defined as before, with a selected imide of the formula Zbeing defined as before, in the presence of formalin, using an alcoholicreaction medium. Synthesis is ordinarily completed in as little as 15minutes when boiling ethanol is the medium of choice.

Corresponding imidoalkyl compounds hereof wherein the alkylene bridgerepresented by T in the generic formula above comprises more than 1carbon can be manufactured by substituting a selected haloalkylimide Hal2 being defined as before, T standing for lower alkylene exclusive ofmethylene, and Hal for chlorine or bromine, and a base such astrimethylarnine, potassium carbonate, or sodium hydroxide, for theimide, formalin, and alcohol called for in the aforesaid manufacture ofimidomethyl products. A ketonic solvent such as butanone is employed ifthe base is a solid.

Conversion of the amine bases of this invention to corresponding acidaddition salts is accomplished by simple admixture of these compoundswith one equivalent of any of various inorganic and strong organicacids, the anionic portion of which conforms to Q as hereinbeforedefined, anhydrous conditions being maintained where the alkylene bridgerepresented by T is a methylene radical.

A variety of means exist for obtaining optically active forms of theproducts of this invention from the racemates which prevail when thestarting materials for the described syntheses are not stereospecific.Products which occur in crystals with apparently differing arrange mentsof the faces can be resolved manually, after the technique pioneered byPasteur. Further, such of the racemates as are fermented by bacteria ormolds will be found to undergo this fermentation at varying rates, andappropriate selections of the microorganisms involved enable isolationof a particular stereochemically pure isomer by destruction of any otherstereomers present.

Alternatively, one can proceed from optically active starting materialsto optically active final products as disclosed in Examples 3-4, 7-8,20, and 23-24 hereafter.

The following examples describe in detail compounds illustrative of thepresent invention .and methods which have been devised for theirmanufacture. However, the invention is not to be construed as limitedthereby, either in spirit or in scope, since it will be apparent tothose skilled in the art of organic synthesis that many modifications,both of materials and of methods, may be practiced without departingfrom the purpose and intent of this disclosure. Throughout the exampleshereinafter set forth, temperatures are given in degrees centigrade andrelative amounts of materials in parts by weight, except as otherwisenoted.

EXAMPLE 1 A. Racemic-S-phenyloxazolidine.To a suspension of 137 parts ofracemic-ot-(aminomethyl)benzyl alcohol in 500 parts of water is addedapproximately 88 parts of aqueous 36% formaldehyde. The resultantmixture is agitated for 10 minutes, during which time an insoluble oilseparates. The oil is extracted with chloroform, and the chloroformextract is then dried over anhydrous sodium sulfate and finally strippedof solvent by distillation at 90-95. The residue thus obtained is thedesired racemic-5-phenyloxazolidine.

B. Racemic 5 plzenyl 3 succim'midomethyloxazolidine.-To a solution ofapproximately 45 parts of 5 racemic-S-phenyloxazolidine andapproximately 30 parts of succinimide in 200 parts of warm absoluteethanol is added 50 parts of aqueous 36% formaldehyde, The resultantsolution is heated at the boiling point under reflux for 15 minutes,then filtered hot. On cooling, the desiredracemic-5-phenyl-3-succinimidomethyloxazolidine is precipitated as acrystalline solid, which is collected on a filter and dried in air. Theproduct has the formula EXAMPLE 2 A. Racemic 4 methyl 5phenylxaz0lidine.-- Substitution of 151 parts of racemic-norephedrinefor the 137 parts of racemic-a-(aminomethyl)benzyl alcohol called for inExample 1A afiords, by the procedure there detailed, racemic 4 methylphenyloxazolidine as a yellow oil, which solidifies on prolongedstanding.

Substitution of 151 parts of racemic-pseudonorephedrine for the 137parts of racemic-m-(aminomethyl)- benzyl alcohol called for in Example1A affords, by the procedure there detailed,racemic-4-methyl-5-phenyloxazolidine as a pale green oil.

Each of the preceding two products is composed of two enantiornorphsindividually diastereemeric with those present in the other product.

B. Racem ic 4 methyl 5 phenyloxazolidine hydrochloride-Theracemic-4-methyl-5-phenyloxazolidine obtained from racemic-norephedrineas detailed in the preceding Part A of this example, upon dissolution inabsolute ethanol and acidification with a slight excess of hydrogenchloride dissolved in 2-propanol, is converted to the hydrochloric acidsalt, which is precipitated by adding anhydrous ether. The colorlesscrystalline racemic-4-methyl-5-phenyloxazolidine hydrochloride whichresults, recovered on a filter and dried in air, melts at 143-148".

C. Racemic 4 methyl 5 phenyl 3succinimidom-ethyloxazolidine.-Substitution of 49 parts of theracemic-4-methyl-5-phenyloxazolidine obtained from racemic-norephedrineas detailed in Part A of this example and 300 parts of absolute ethanolfor the 45 parts of racemic-S-phenyloxazolidine and 200 parts ofabsolute ethanol, respectively, called for in Example 1B affords, by theprocedure there described, racemic-4-methyl-5-phenyl-3-succinimidomethyloxazolidine as a white crystalline solidmelting at l32l34.

Substitution of 49 parts of the racernic-4-methyl-5- phenyloxazolidineobtained from racemic-pseudonorephedrine as detailed in Part A of thisexample for the 45 parts of racemic-S-phenyloxazolidine called for inExample lB 'afiords, by the procedure there described, racemic 4 methyl5 phenyl 3 succinimidomethylgrsrazolidine as a white crystalline solidmelting at 70.5-

Each of the two products is composed of two enantiomorphs individuallydiastereomeric with those present in the other product. The productshave the formula C oW LN I 6 EXAMPLE 3 A. Dextro 4 methyl 5phenyl0xaz0lidine.-Substitution of 151 parts of dextro-norephedrine forthe 137 parts of racemic-a-(aminomethyDbenzyl alcohol called for inExample 1A affords, by the procedure there de tailed,dextro-4-methy1-5-phenyloxazolidine .as a colorless oil with a specificrotation, referred to the sodium D line, of +17.9 in methanol solution.

B. Dextr0-4-m ethyl 5 phenyloxazolidine hydrochloride-Thedextro-4-methyl-5-phenyloxazolidine obtained from dextro-norephedrine asdetailed in the preceding Part A of this example, upon dissolution inabsolute ethanol and acidification with a slight excess of hydrogenchloride dissolved in 2-propanol, is converted to the hydrochloric acidsalt, which is precipitated by adding anhydrous ether. The colorlesscrystalline deXtro-4-methyl- S-phenyloxazolidine hydrochloride whichresults, filtered oil and recrystallized from a mixture of absoluteethanol and ether, melts at 1715-174 and has a specific rotation,referred to the sodium D line, of +47.1 in methanol solution.

C. Dextr0-4-methyl-5phenyl-3-succinimid0methyl 0xazolidine-Substitutionof 49 parts of the dextro-4-methyl- S-phenyloxazolidine obtained fromdextro-norephedrine as detailed in Part A of this example and 320 partsof absolute ethanol for the 45 parts of racemic-S-phenyloxazolidine and200 parts of absolute ethanol, respectively, called for in Example 1Bafiords, by the procedure there described,dextro-4-methyl-5-phenyl-3-succinimidomethyloxazolidine as a whitecrystalline solid melting at 99-101 and with a specific rotation,referred to the sodium D line, of +8.7 in methanol solution.

EXAMPLE. 4

A. L'ev0-4-methyl'5 phenyloxazolidine.Substitution of 183 parts oflevo-norephedrine and 101 parts of aqueous 36% formaldehyde for the 137parts of racemic-a- (aminomethy1)-benzyl alcohol and 88 parts of aqueous36% formaldehyde, respectively, called for in Example 1A affords, by theprocedure there detailed, levo-4 -methyl- 5-phenyloxazolidine as acolorless oil characterized by a specific rotation, referred to thesodium D line, of 16.9 in methanol solution.

Substitution of 151 parts of levo-pseudonorephedrine for the 137 par-tsof racemic-ot-(aminomethyl)benzyl alcohol called for in Example 1Aafiords, by the procedure there detailed,levo-4-rnethyl-S-phenyloxazolidine as a colorless oil characterized by aspecific rotation, referred to the sodium D line, of 59.7 in methanolsolution.

The two products are diastereomers.

B. Lev0-4-methyl-5-phenyl-3-succinimid0methyloxazol- Mine-Substitutionof 49 parts of the levo-4-rnethyl-5- phenyloxazolidine obtained fromlevo-norephedrine as detailed in the preceding Part A of this exampleand 280 parts of absolute ethanol for the 45 parts of racemic-S-phenyloxazolidine and 200 parts of absolute ethanol, respectively,called for in Example 13 affords, by the procedure there described,levo-4-methyl-5-phenyl-3-succin-i rnidomethyloxazolidine as whitecrystalline flakes melting at 9799.5 and with a specific rotation,referred to the sodium D line, of 2.9 in methanol solution.

Substitution of 49 parts of the levo-4-methyl-5-phenyloxazolidineobtained from levo-pseudonorephedrine as detailed in the preceding PartA of this example and 280 parts of absolute ethanol for the 45 parts ofracemic-S- phenyloxazolidine and 200 parts of absolute ethanol,respectively, called for in Example 113 affords, by the procedure theredescribed, levo-4-methyl-5-phenyl-3-succinimidomethyloxazolidine as awhite crystalline solid melting at 7477.5 and With a specific rotation,referred to the sodium D line, of -57.6 in methanol solution.

The two products are diastereomers.

EXAMPLE 5 Racemic-3-glumrimtcldmethyl-4-methyl-5 phenyloxa- 7zolidine.To a solution of approximately 49 parts of theracemic-4-methyl-S-phenyloxazolidine obtained from race-Inic-norephedrine as detailed in Example 2A and 35 parts of glutarimidein 200 parts of Warm absolute ethanol is added 50 parts of aqueous 36%formaldehyde. The resultant solution is heated at the boiling pointunder reflux for 15 minutes, then filtered hot. The hot filtrate isdiluted with water to the point of incipient precipitation. On cooling,the desired racemic-3-glutarimidomethyl-4- methyl-5-phenyloxazolidine isprecipitated. It melts at 92-94 and has the formulaRacemz'c-3-(fi-ethyl-B methylglutarimidomethyl) 4-methyI-S-phenyloxazolidine.--Substitution of 48 parts offi-ethyl-fi-methylglutarirnide and 280 parts of absolute ethanol for the35 parts of glutarimide and 200 parts of absolute ethanol, respectively,called for in Example 5 affords, by the procedure there detailed,racemic-3-(fi-ethyl- [3 111ethylglutarimidomethyl)-4-methyl 5phenyloxazolidine as a White crystalline solid melting at 7376.

To a solution of approximately 49 parts of the racemic-4-methyl-S-phenyloxazolidine obtained from racemic-pseudonorephedrine asdetailed in Example 2A and 48 parts of S-ethyl-fi-methylglutarirnide in200 par-ts of Warm absolute ethanol is added 50 par-ts of aqueous 36%formaldehyde. The resultant solution is heated at the boiling pointunder reflux for 15 minutes, then chilled and finally filtered. Dilutionof the filtrate with 100 parts of water, followed by refrigeration at-5, causes precipitation of racemic-3-(fl-ethyl-Bmethylglutarimidomethyl) 4- methyl-S-phenyloxazolidine as a whitecrystalline solid melting at 86-88.

Each of the two products is composed of two enantiomorphs individuallydiastereomeric with those present in the other product. The productshave the formula EXAMPLE 7 Dexzro 3 ethyl p methylglutarimidometlzyl)-4-methyl-5-phenyloxazolidine.Substitution of 49 parts of thedextro-4-methyl-5-phenyloxazolidine obtained from dextro-norephedrine asdetailed in Example 3A, 48 parts of fi-ethyl-fi-methylglutarimide and280 parts of absolute ethanol for the 49 parts of racemic-4-methyl-5-phenyloxazolidine, 35 parts of glutarimide, and 200 parts of absoluteethanol, respectively, called for in Example 5 afiords, by the procedurethere described, dextro-3-(flethyl-fi-methylglutarirnidomethyl) 4methyl-S-phenyloxazolidine as a White crystalline solid melting at 93-95and further characterized by a specific rotation, referred to the sodiumD line, of +28.3 in methanol solution.

8 EXAMPLE 8 Levo 3 (,8 ethyl [3 methylglutarimidomethyl)-4-metlzyl-5-phenyloxazolidine.-Substitution of 49 parts of thelevo-4-methyl-S-phenyloxazolidine obtained from levo-norephedrine asdetailed in Example 4A, 48 parts of fl-ethyl-fi-methylglutarimide, and280 parts of absolute ethanol for the 49 parts ofracemic-4-methyl-5-phenyloxazolidine, 35 parts of glutarimide, and 200parts of absolute ethanol, respectively, called for in Example 5affords, by the procedure there described, levo-3-(fi-ethyl-,B-methylglutarimidomethyl) 4 methyl 5 phenyloxazolidine as a whitecrystalline solid melting at 91-94 and with a specific rotation,referred to the sodium D line, of 23.2 in methanol solution. Thisproduct is the enantiomorph of the product of Example 7.

EXAMPLE 9 mula $11: N o=f To EXAMPLE 10 A. Racemic 5 (4 chlorophenyl) 4methyloxazolidine.Substiltution of 358 parts ofracemic-u-(laminoethyl)-4-chlorobenzyl alcohol, 163 parts of aqueous 36%formaldehyde, and 1000 parts of water for the 137 parts ofracemic-a-(aminomethyl)benzyl alcohol, 88 parts of aqueous 36%formaldehyde, and 500 parts of water, respectively, called for inExample 1A affords, by the procedure there detailed,racemic-S-(4-chlorophenyl)- 4-methyloxazolidine as a light brown oil.

B. Racemic 5 (4 chlorophenyl) 4methyl-3-succinimidomethyloxazolidine.Substitution of 59 parts ofracemic-S-(4-chlorophenyl)-4-methyloxazolidine for the 45 parts ofracemic-5-phenyloxazolidine called for in Example 1B alfords, by theprocedure there detailed, racemic-S-(4-chlorophenyl)-4-methyl 3succinimidomethyloxazolidine which, recrystallized from absoluteglutarimide, respectively,

EXAMPLE 11 mula EXAMPLE 12 A. Racemic -(4 methoxyphenyl) 4methyloxaz0lidine.--Substitution of 300 parts ofrace-mic-a-(laminoethyl)-4-methoxybenzyl alcohol and 117 parts ofaqueous 36% formaldehyde for the 137 parts ofracemicu-(aminomethyDbenzyl alcohol and 88 parts of aqueous 36%formaldehyde, respectively, called for in Example 1A affords, by theprocedure there detailed, racemic-S-(4-met-hoxyphenyl)-4-methyloxazolidine as a yellow oil.

B. Racemic 5(4-meth0xyphenyl)-4-methyl-3-succinimidomethyl0xaz0lidine.Substitutionof 58 parts of racemic 5 (4-rnethoxpyhenyl)-4-methyloxazolidine for the45 partsof racernic-Swphenyloxazolidine called for in Example 1Baffords, by the procedure there detailed, racemic 5 (4 -methoxyphenyl)4-methyl-3-succinimidomethyloxazolidine which, recrystallized fromabsolute ethanol, is obtained as white needles melting at 103105.

The product has the formula EXAMPLE 13 A.Racemic-S-(3,4,5-trimethoxyphenyl)-4-methyl-0xazolidine.Substitution of241 parts of racemic-u-(laminoethyl)-3,4,5-trimethoxybenzyl alcohol forthe 137 parts of racemic-u-(aminomethyl)benzyl alcohol called for inExample 1A affords, by the procedure there detailed, racemic 5 (3,4,5-trimethox.yphenyl) -4-methyloxazolidine.

B. Racemic 5 -(3,4,5-trimethoxyphenyl)4 methyl-3-succinim'idomethyloxaz0lidine.--Substitution of 76 parts ofracemic-S-(3,4,5-trimethoxyphenyl)-4 methyl-oxazolidine and 30 parts ofsuccinimide for the 49 parts of racernic-4-methyl-5-phenyloxazolidineand 35 parts of glutarimide, respectively, called for in Example 5affords, racemic- 4- methyl-5-phenyloxazolidine and 35 parts of calledfor in Example 5 aflords,

by the procedure there detailed, racemic-5-(3,4,5-tri- 1 0methoxyphenyl) 4 methyl-3-succinimidomethyloxazolidine. The product hasthe formula HaCtg HaO -N 5 Hz a 0=' To EXAMPLE 14 r A. Racemic 5-(3,4-diethoxy phenyl -4-methyl-0xaz0lidine-Substitution of 239 parts ofracemic-u-(l-arninoethyl)3,4-diethoxybenzyl alcohol for the 137 parts ofracemic-a-(aminomethyl)benzyl alcohol called for in Example lA afiords,by the procedure there detailed, racemic-5 3 ,4-diethoxyphenyl)-4-methyloxazolidine.

B. Racemic 5 (3L4-dieth0xyphenyl)-4-methyl-3-suacinimidomethyloxazo[Mine-Substitution of 75 parts ofracemic-S-(3,4 diethoxyphenyl)-4methyloxazolidine and 30 parts ofsuccinimide for the 49 parts of racemic-4-methyl- 5-phenyloxazolidineand 35 parts of glutarimide, respec tively, called for in Example 5affords, by the procedure there detailed,racemic-5-(3,4-diethoxyphenyl)-4methyl- 3-succinimidomethyloxazolidine.The product has the formula libero-( 31 W EXAMPLE 16Racemic-3-maleimid0methyl-4-methyl-5-phenyloxazolidine-Substitution of49 parts of the racemic-4-methyl-5- phenyloxazolidine obtained fromracemic-norephedrine as detailed in Example 2A and 30 parts ofmaleimidefor the 45 parts of racemic-S-phenyloxazolidine and 30 parts ofsuccinimide, respectively, called for in Example 18 affords, by theprocedure there described, racemic-S-maleimidomethyl-4-methyl-5-phenyloxazolidine. The product is obtained aswhite needles melting at 99-102".

Substitution of 49 parts of the racemic-4-methyl-5- formula EXAMPLE 17 lT T EXAMPLE 1 8 Racemzc-3-maleimid0methyl-4-meIhyl-5-(4 methoxyphenyl)oxazolidine.Substitution of 58 parts of racemic--(4-rnethoxyphenyl) 4methyloxazolidine and 30 parts of maleimide for the 45 parts of:raceInic-5pheny1- oxazolidine and 30 parts of succinimide,respectively, called for in Example 1B affords, by the procedure theredescribed, racernic-3-malei1nidomethy1 4 methyl-5-(4- methoxyphenyl)oxazolidine which, recrystallized from absolute ethanol, is thrown downas ofi-white needles melting at 'll6119. The product has the formulaEXAMPLE 19 Racemic 3 (cyclohexane 1,2 dicarboximido) -4-methyl-S-phenyloxazolidine.Substitution of 47 parts ofrcyclohexane-1,2-dicanboximide and 280 parts of absolute ethanol for the35 parts of glutarimide and 200 parts of absolute ethanol, respectively,called for in Example 5 affords, by the procedure there described,racemic-3- (cyclohexane-1,2-dicarboximido)-4-methyl 5 phenyloxazolidineas a colorless crystalline solid melting at 64- 68". The product has theformula EXAMPLE 2O Lev0-3-(cyclohexane-1,2-dicarboximido)-4-methyl 5-phanyloxazoMina-Substitution of 35 parts of the levo- 4 methyl 5phenyloxazolidine obtained from levonorephedrine as detailed in Example4A, 33 parts of cyclohexane-1,2-dicarboximide, 38 parts of aqueous 36%formalin, and 280 parts of absolute ethanol for the 45 parts ofracemic-S-phenyloxazolidine, 30 parts of succinimide, 50 parts ofaqueous 36% formaldehyde, and 200 parts of absolute ethanol,respectively, called for in Example 1B affords, by the procedure theredescribed levo-3-(cyclohexane-1,2-dicarboximido) 4 methyl -5-phenyloxazolidine as a colorless crystalline solid melting at 5562. Theproduct is further characterized by a specific rotation, referred to thesodium D line, of 2.l in methanol. It is one of the two enantiomorphswhich compose the product of Example 19.

EXAMPLE 21 Racemic3-(I-cyclohexene 4,5 dicarboximido) 4-methyI-S-phenyloxazolidine.Substitution of 49 parts of theracemic-4-methyl-5-phenyloxazolidine obtained from raccmic-norephedrineas detailed in Example 2A, 46 parts of 1=cycloheXene-4,S-dicarboximide,and 280 parts of absolute ethanol for the 45 parts ofracemic-S-phenyloxazolidine, 30 parts of succinimide, and 200 parts ofabsolute ethanol, respectively, called for in Example 1B affords, :bythe procedure there described, racemic-3-(1-'cyclohexene-4,S-dicarboximido) 4 methyl 5 phenyloxazolidine as anoff-white solid melting at 98.5100.5.

Substitution of 49 parts of the racemio-4-methyl-5- phenyloxazolidineobtained from racemic-pseudo-norephedrine as detailed in Example 2A and46 parts of 1- 'cyclohexene-4,5-dicarboxirnide for the 49 parts ofracemic-4-rnethyl-s-phenyloxazolidine and 35 parts of glutarirnide,respectively, called for in Example 5 affords, by the procedure theredescribed, racerm'c-3-(1-cyclohexene4,S-dicarboxirnido)-4-met hy1 5phenyloxazolidine as an off-White solid melting at 92.5.

Each of the two products of this example is composed of twoenantiornorphs individually diastereomeric with those present in theother product. The products have the formula EXAMPLE 22Racemz'c-4-n1ethyl 5 phenyl 3 phthalimidomethyloxazolidine.-Substitutionof 45 parts of phthalimide, 49 parts of theracemic-4-methyl-5-phenyloxazolidine obtained from racemic-norephedrineas detailed in Example 2A, and 600 parts of absolute ethanol for the 45parts of racemic-S-phcnyloxazolidine, 30 parts of succinirnide, and 200parts of absolute ethanol, respectively, called for in Example 1Baffords, by the procedure there described, racemic 4 methyl 5phenyl-S-pihthalimidomethyloxazolidine as a colorless crystallineproduct melting at Ill-113.

Substitution of 49 parts of the racemic-4-nrethyl-5- phenyloxazolidineobtained from racemic-pseudonorephedrine as detailed in Example 2A and45 parts of phthalimide for the 45 parts of racemic-S-phenyloxazolidineand 30 parts of succinicide, respectively, called for in Example 1Baitords, by the procedure there described, racemic 4 methyl-S-phenyl 3phthalimidomethyloxazolidine as a white powder melting at 91.5-94.5.

Each of the two products of this example is composed of twoenantiomorphs individually diastereomeric with those present in theother product. The products have the formula EXAMPLE 23 Dextr 4-methyl 5phony[-3-ph thalimidomethyloxazolidine-Substitution of 43 parts oflevo-4-methyl-5- phenyloxazolidine obtained from levo-norephedrin as detailed in Example 4A, 40 parts of phthalimide, 44 parts of aqueous 36%formaldehyde, and 400 parts of absolute ethanol for the 45 parts ofnacemic-S-phenyloxazolidine, 30 parts of succinimide, 50 parts ofaqueous 36% formaldehyde, and 200 parts of absolute ethanol,respectively, called for in Example 113 afiords, by .the procedure theredescribed, dextro 4 methyl-S-phenyl 3 phthalimidomethyloxazolidine as awhite crystalline solid melting at 106.5 8.5. The product is furthercharacterized by a specific rotation, referred to the sodium D line, of+6.2 in methanol solution. It is one of the two enantiomorphs whichcompose the racemic-4-methyl-5-phenyl-3- phthalimidomethyloxazolidinemelting at Ill-413 and described in Example 22.

EXAMPLE 24 EXAMPLE 25 Racemic-S (4-chlorophenyl)-4-methyl-3-phthaiimid0-methyloxaz0lidine.-Substitution of 59 parts of nacemic-5-(4-chlorophenyl)-4-methyloxa2iolidine and 45 parts of phthalimide forthe 45 parts of racemic-S-phenyloxazoli- .dine and 30 parts ofsucoinimide, respectively, called for inExamp'le 1B affords, by theprocedure there described, racemic-5-(4 chlorophenyl) 4methyl-3-phthalimidomethyloxazolidine as white needles melting at -118".The product has the formula V moo-Gr EXAMPLE 27 A. Racemic 5 cyclohexyl4 methyloxaz0lidz'ne.- Substitution of 79 parts ofracemic-a-(l-aminoethyDcyclohexancmethanol, 44 parts of aqueous 36%formaldehyde, and 250 parts of water for the 137 parts of racemic-u-(aminomethyl)benzyl alcohol, 88 parts of aqueous 36% formaldehyde, and500 parts of Water, respectively, called for in Example 1A affords, bythe procedure there described racemic-S-cyclohexyl-4-methy1oxazolidineas a light brown oil which partially solidifies on prolonged standing.

B. Racemic-5-cyclohexyl -4 -methyloxazalidine hyd-r0 chl0ride.Theracemic-S-cyclohexyl-4-methyloxazolidine obtained by the procedure ofthe foregoing Part A of this example, upon dissolution in absoluteethanol and acidification with a slight excess of hydrogen chloridedissolved in 2-propanol, is converted to the hydrochloric acid salt,which is precipitated by adding anhydrous ether. The colorlesscrystalline rac'emi'c-S-cyclohexyl-4-methyloxazolidine hydrochloridewhich results melts at 1375- 140.

0, Racemic-5-cycl0hexyl-4-methy'l 3succinimidontethyloxwzolidine.--Substitution of 51 parts of racemic-5-cyclohexyl-4-methyloxazolidine, 30 parts of succinimide, and 400 partsof absolute ethanol tor the 49 parts ofracemc-4-methyl-5-phenyloxazolidine, 35 parts of glutarimide, and 200parts of absolute ethanol, respectively,

called for in Example 5 affords, by the procedure there described,racemiC S-cycloihexpl4methyl-3-sucoinimido methyloxazolidine as a whitecrystalline solid melting at 73-75. The product has the formula Ha C-N15 EXAMPLE 28 Racemic-S-cyclohexyl-3-maleimidomethyl 4 melhyloxazolidine.Substitution of 51 parts ofracemic-S-cyclohexyl-4-methyloxazolidine and 30 parts of maleimide forthe 45 parts of racemic-S-phenyloxazolidine and 30 parts of succinimide,respectively, called for in Example 13 affords, by the procedure theredescribed, racemic-5-cyclohexyl-S-maleimidomethyl-4-methyloxazolidinewhich, recrystallized from absolute ethanol, melts at 82.5-88. Theproduct is a green-yellow solid. It has the formula Hil 5 EXAMPLE 29Racemic-S-cyclohexyl-4-methyl-3phtlmlimidometlzyloxaZolidina-Substitution of $1 parts ofracemic-S-cyclohexyl-4-methyloxazolidin'e, 45 parts of phthalimide, and600 parts of absolute ethanol for the 45 parts of racernic-5-phenyloxazolidine, 30 parts of succinimide, and 200 parts of absoluteethanol, respectively, called for in Example lB affords, by theprocedure there described, racemic=5-cyclohexyl-4-methyl 3phthalimidomethyloxazolidine as a colorless crystalline solid melting at905-93 The product has the formula What is claimed is: l. A member ofthe class consisting of dextro, levo, and racemic compounds of theformula CHz-Z wherein R represents a member of the class consisting ofphenyl, halophenyl, (lower alkoxy)phenyl, poly(lower alkoxy)phenyl, andcyclohexyl; X represents a member of the class consisting of hydrogenand lower alkyl; and Z represents a member of the class consisting ofsuccininn'do, glutarimido, fi-methy-l-B ethylglutarimido, maleimido,cyclohexanel,Z-dicarboximido, 1-cyclohexene-4,5 dicarboximido, andphthalimido.

2. A compound of the formula uill N "i T" 3. Dextro-4-methyl-5-phenyl 3succinimidomethyloxazolidine.

4. A compound of the formula 0 Halogen-Q 7 5Racemic-S-(4-chlorophenyl)-4-methy1-3 -succinimidomethyloxazolidine.

6. A compound of the formula O (lower alkoxy N of To wherein n is apositive integer amounting to less than 4.

7. Racernic-S-(4-methoxyphenyl)4-methyl-3-succinirnidomethyloxazolidine.

8. Racemic 3 maleimidomethyl-4-methyl-5-phenyloxazolidine.

9. A compound of the formula wherein R represents a member of the classconsisting of phenyl, halophenyl, (lower alkoxy)phenyl, poly(loweralkoxy)phenyl, and cyclohexyl; X represents a member of the classconsisting of hydrogen and lower alkyl; and Z represents a member of theclass consisting of succinimido, glutarimido,fl-methyl-fi-ethylglutarimido, maleimido, cyclohexane-1,2-dioarboximido,1-cyc1ohexene-4,5- dicarboximido, and phthalimido, the step whichcomprises heating an oxazolidine of the formula wherein R and X aredefined as before, with an imide of the formula Z being defined asbefore, in the presence of aqueous formaldehyde, using alcohol assolvent.

13. A compound of obe formula 14. A compound of -the formula 15. Acompound of the formula No references cited.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,081,308 March 12, 1963 Max J. Ka lm It is hereby certified that errorappears in the above numbered patent requiring correction and that thesaid Letters Patent should read as 1 corrected below Column 6, line 38,for "(aminomethyD-benzyl" read (aminomethyDbenzyl column 9. lines 73 and74, strike out "racemic-A-methyl-5-phenyloxazolidine and 35 parts ofglutarimide, respectively, called for 1n Example 5 aifords,"; column 10,line 15, for "-methyl-oxazoli" in italics, read -methyloxazoli initalics; column 11, line 26, for '(chl0rophenyl)" read (4-chlorophenyl)column 12, line 46, for "-pseudo-nor read pseudonorcolumn 13, line 10,for "succinicide" read succinimide Signed and sealed this 31st day ofMarch 1964.

aEAL) ttCStZ ERNEST w SWI EDWARQ I BRENNER \ttesting OfficerCommissioner of Patents

1. A MEMBER OF THE CLASS CONSISTING OF DEXTRO, LEVO, AND RACEMICCOMPOUNDS OF THE FORMULA
 13. A COMPOUND OF THE FORMULA